Nathan Goldstein, MD

Associate Professor

Chief, Division of Pal l iative Care ,

Mount Sinai Beth Israel

Director of Research and Qual i ty

Hertzberg Pal l iat ive Care Insti tute

Brookdale Department of Geriatr ics Pal l iat ive Medicine

Icahn School of Medicine at Mount Sinai

September 25, 2015

NPCRC

NUTS AND BOLTS OF MULTI-

SITE RCTS IN PALLIATIVE CARE

No relevant financial conflicts to disclose.

This is not science …. one man’s highly

opinionated account of a journey with an RCT.

DISCLOSURE /

ACKNOWLEDGEMENTS

Setting up your trial: Choosing your sites Writing your grant Primary and Secondary outcomes Budget

Good news and bad news: you got the grant

Project Management Multi Site IRBs Data collection systems Protocol Manual Opening / training meetings DSMB / DSMP ClinicalTrials.Gov

Challenges once underway

Enrollment, enrollment, enrollment

Modifications big and small

Rethinking some beginning assumptions

OUTLINE

WISDOM TRIAL

WISDOM TRIAL

Working to Improve discuSsion about DefibrillatOr Management

5-year RCT of a clinician-centered patient counseling intervention to improve communication between heart failure clinicians and patients with ICDs

Randomized by hospital; intervention focused on heart failure clinician; and the patient / caregiver unit of analysis

Funded by R01 HL102084 - in year 5

WISDOM INTERVENTION

Small group sessions with heart failure

clinicians to improve communication skills

Automatic reminder system before patient

encounters (inpatient and outpatient)

Aggregated feedback to clinicians about their

individual performance

WISDOM TEAM

Sinai UC Denver

Nathan Goldstein, MD Jean Kutner, MD

Sean Morrison, MD Dan Matlock, MD

Sean Pinney, MD Amy Jenkins

Drew Helmus

Chris Espina

Mayo Penn

Jake Strand, MD Matt Hutchinson, MD

Alex Fiksdal Faith Pickering

Caroline Olt

Montefiore Yale

Hannah Lipman, MD Rachel Lampert, MD

Camille Gonzalez Theresa Donovan

WISDOM HIDDEN OBJECTIVE

Encourage clinicians to discuss larger goals of

care

Not just about management of ICD

What patients want given their stage of illness

Tailor treatments to those goals, including

management of ICDs

Trying to change clinician behavior

NOT to have every ICD turned off

SETTING UP YOUR TRIAL

This may seem obvious…but….

This is the most important part of your study

Its ultimate success depends on this

Find a place where:

You can get population you need

Have on-site colleagues that will advocate for your

study

Have on-site colleagues with research background

(not required but it makes your life soooo much easier)

Work on this well in advance!

CHOOSING YOUR SITE

Don ’t overpromise

Think very carefully about your power calculations

I don’t mean the math. Is the number you want actually

achievable?

Make it clear how you are communicating with sites on an

ongoing basis

Make it easy for the reviewers

WRITING YOUR GRANT

Standardization, standardization, standardization

How are you going to do the same thing at every

site?

We are rarely drug A vs. drug B, which is easy to

standardize

Important for review, implementation, and

generalizability

MULTI SITE INTERVENTIONS

Primary and secondary are your aims

Extra are what you are going to fall back on if

primary and secondary don ’t work

Good for future learners

However avoid the “it would be interesting if we….”

Think about temporal trends

Where is the field going to be in X years?

OUTCOMES: PRIMARY, SECONDARY, EXTRA

Assuming you are going for an NIH R01, your cap is $500K

Turns out that ’s nothing

Especially after a 10-20% cut that you are going to get

“I never even consider going in for that little.”

A co-investigator colleague of mine

Going above the NIH cap means you have to go to NIH to plead

your case in advance of submitting your grant

I regret not doing this

NIH $500K ANNUAL CAP

How will you motivate the sites?

Flat fee per site to fund research coordinator?

By enrollment?

You need a project manager who will do the day to

day work of your trial!

This person will know more about the trial than you

do

Not the place to save money in the budget

BUDGETING

GOOD NEWS AND BAD NEWS:

YOU GOT THE GRANT

If you think your IRB is bad… or inconsistent….

Helpful to get your IRB approved first

More convincing argument to the other IRBs

Some wont even review until the prime site is approved

1:1 meetings with chair of your IRB or with other IRBs

E.g. one of our sites spent 6 months getting IRB approval which was

resolved with a 30 minute Skype call

MULTIPLE SITE IRBS

Need a web-based single system

People SAY they want to enter online in real time…but…

Build checks into system

Our system emails us about every death, hospitalization, and new

enrollment. Also emails us when a patient is voided / removed from

system.

System is color coded so when a patient isn’t completed or

something isn’t completed it is a different color on the research

coordinator’s screen

DATA COLLECTION

Need a protocol manual that your research

coordinators can follow, that you will update

over the course of the study

Tremendous effort in the beginning, but will

last you for X years so put the time in

PROTOCOL MANUAL

Bring all of your people together for 1 -2 days

Builds team rapport, but also allows you to standardize training

Have your MOP and Data Collection system set up

Hint: build ramp up into your timeline, for us this was month 6 of the grant period

Think about how you will build in continued training when staff leave, refreshers

OPENING TRAINING

Data and Safety Monitoring BOARD vs. Data and Safety Monitoring Plan

A Board is an outside entity that you can suggest in your application but your institute approves/invites Their role is to monitor safety of subjects

Set up separate from advisors/mentors/investigators

Can stop the trial for safety (in a good way or a bad way)

A Plan is an outline of how you will assure safety of subjects at every step of the way The PI can be the head of a dsmP not a dsmB

This is for lower risk trials and makes your life easier

Consult with your program officer before you submit because this can actually prevent you from getting funded (human subjects concerns DO affect your score)

DSMB VS DSMP

Essential

Painful at first (sooo many questions……)

12 sections

Blank application is 22 pages

Only do once, update yearly with a single line email stating whether there are changes

CLINICAL TRAILS . GOV

The progress report is straightforward

You must rebudget and get new subcontracts every

year. This will make you want to kill yourself.

PLAN AHEAD!!!! THIS WILL TAKE 4-6 WEEKS!

The progress report is due 3 months before the year

ends.

Carry over is a wonderful thing. If you have more

than 25% you are in trouble.

PROGRESS REPORTS

CHALLENGES ONCE

UNDERWAY

By far the most dif ficult and ongoing challenge

Prime site is always going to be more motivated than others

If NIH they watch this like a hawk – some institute to institute variation

ENROLLMENT, ENROLLMENT,

ENROLLMENT

SITE ENROLLMENT

Sinai 125

2 49

3 103

4 99

5 76

6 79

Your Institute will ask for a milestone

recruitment plan. They will then track your

progress against this chart.

This chart keeps me up at night.

No, really, this chart keeps me up at night.

MILESTONE RECRUITMENT PLAN

https://www.nhlbi.nih.gov/research/funding/human-subjects/accrual-guidelines#Studies

IRB Modifications are the norm

Adding people, making minor changes in data

collection forms, adding questions you forgot

Remember that a modification has to go through all

of your sites – which means you want to batch them

to make things easier for the sites

MODIFICATIONS BIG AND SMALL

“This is clinical research in the real world.”

– Henry Sachs, MD

Once you start you will see that there are some huge things that need to change, but that is the way it works

Originally only included people who were NOT VAD and transplant candidates

Created a group of patients > 70 who were not generalizable because they weren’t considered for advanced therapies

Seattle Heart Failure was not performing well and too difficult to find, so broadened entry criteria

Originally excluded Spanish speakers

Is the spirit of the research the same? Are you improving the quality of the finished product?

RETHINKING BASIC ASSUMPTIONS

GOOD LUCK!

Nathan.Goldstein@mssm.edu